The semaphorin family of membrane proteins was initially characterized as axon-guidance molecules critical for neuronal development. It is now recognized that they play critical roles in a number of physiological and pathologic responses including angiogenesis, cancer, and inflammation by binding to a diverse array of counter receptors. Recent studies suggest that semaphorins can act as co-stimulatory molecules. Sema4A was previously shown to be an important co-stimulatory molecule for T-cell activation in vitro and for Th1-inflammation in vivo. Sema4A was shown to control the Th1/Th2 balance. However, we recently demonstrated that Sema4A played a down-regulatory role during allergic (Type II) inflammation in vivo. We observed increased allergic airway inflammation accompanied by increased IL- 13 and lower Treg numbers in allergen-treated Sema4A-/- mice compared to WT mice. Interestingly, allergic inflammation was significantly reduced by a single administration of recombinant soluble Sema4A. Based on these results, we propose that Sema4A is a negative regulator of Th2-driven responses. However, the mechanism by which Sema4A dampens allergic inflammation is unknown. We hypothesize that Sema4A limits allergic inflammation by enhancing regulatory T-cell numbers, in addition to acting on resident lung cells. The specific aims of this proposal designed to test these hypotheses are: 1) to define the Sema4A receptor(s) responsible for its control of T cell responses in allergic inflammation, 2) to evaluate the contribution of Plexin B1 to the suppressive activity of Sema4A, and 3) to analyze the ability of specific Sema4A mutants to interact with counter receptors and suppress allergic inflammation.